Caveolin-1 Is Down-Regulated in Human Lung Carcinoma and Acts as a Candidate Tumor Suppressor Gene

proteins was tested for reactivity with antibodies in the sera of cancer patients and the sera of healthy subjects. Differences in fluorescent intensity showed an ability to distinguish between them. Our data show the feasibility of profiling antibody responses as markers of disease and are proof of the concept that supports the rationale for further development of this approach. The potential for efficient profiling of patient sera for tumor-associated antibodies makes this work both logical and timely.

Caveolin-1 Is Down-Regulated in Human Lung Carcinoma and Acts as a Candidate Tumor Suppressor Gene* Martin M. Be´ langer, MS; E´ lise Roussel, MS; and Jacques Couet, PhD

tumors. This caveolin expression was not related to tumor type, response to treatment, sex, or therapy regimen. Interestingly, in several drug-resistant cancer cells, a strong induction of caveolin-1 expression has been reported, suggesting a role for caveolin-1 in the acquisition and/or the maintenance of the multidrug resistance phenotype. In order to better understand the observation in human lung tumors, we treated drug-sensitive lung cancer cells (ie, A549, Calu-6, or NCI-H69 cells) with various cytotoxic drugs (ie, taxol, doxorubicin, or etoposide). Exposure to chemotherapeutic agents was sufficient to strongly up-regulate both caveolin-1 and caveolin-2 messenger RNA and protein levels. This up-regulation was sustained even a week after drug removal. The upregulation of caveolin expression was dose-dependent. Our results suggest that caveolin-1 has tumor suppressor activity and is down-regulated during the development of lung cancer. Caveolin up-regulation is an early cellular response to a cytotoxic stress taking place well before drug resistance is manifested.

(CHEST 2004; 125:106S) expression is down-regulated in oncogeniC aveolin-1 cally transformed fibroblasts as well as in breast and

lung carcinoma cell lines. In the present study, we studied by immunohistochemistry the expression of caveolin-1 and caveolin-2 proteins in primary non-small cell lung tumors of human origin. All tumor specimens tested were negative for both caveolins in patients who had not undergone neoadjuvant therapy prior to surgery (32 of 32 patients). Both caveolin-1 and caveolin-2 were abundantly expressed in the tissue surrounding the tumors. Fibroblasts, alveolar epithelial cells, smooth muscle cells, and endothelial cells were all positive for caveolins. In order to better understand the potential effects on lung cancer cells of this caveolin induction, we expressed caveolin-1 complementary DNA in a lung adenocarcinoma cell line (Calu-6). In cancer cells overexpressing caveolin-1, proliferation was strongly reduced. We also observed a sharp decrease in cell motility after caveolin-1 expression in Calu-6 cells. However, no changes were observed in terms of sensitivity to cytotoxic drugs. We also studied a subset of primary lung tumors from patients who were treated prior to surgery with various regimens of chemotherapy and/or radiotherapy. In this particular population, 50% of patients (7 of 14 patients) showed both caveolin-1 and caveolin-2 expression in their *From the Unite´ de Recherche en Pneumologie, Institut Universitaire de Cardiologie et de Pneumologie de l’Universite´ Laval, Centre de Recherche Hoˆ pital Laval, Sainte-Foy, QC, Canada. Supported by the Fondation J.D. Be´ gin and Le Re´ seau en Sante´ Respiratoire (RSR) du Fonds de la recherche en Sante´ du Que´ bec. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Jacques Couet, PhD, Unite´ de Recherche en Pneumologie, Institut Universitaire de Cardiologie et de Pneumologie de l’Universite´ Laval, Centre de Recherche Hoˆ pital Laval, 2725 Chemin Sainte-Foy, Sainte-Foy, QC, G1V 4G5 Canada; e-mail: [email protected] 106S

Retrovirus-Induced Lung Cancer* Mechanisms of Transformation of Alveolar Type II Epithelial Cells James C. DeMartini, DVM, PhD; Judy A. Platt; Amanda Evans; Dennis R. Voelker; and Thomas E. Allen

(CHEST 2004; 125:106S–107S) Abbreviations: ATII ⫽ alveolar type II; JSRV ⫽ jaagsiekte sheep retrovirus

sheep retrovirus (JSRV) is the causative T heagentjaagsiekte of ovine pulmonary adenocarcinoma, which is the only known example of a retrovirus-induced lung cancer. The finding that the JSRV env gene is sufficient to induce the transformation of murine and avian fibroblast cell lines has led to an investigation of the mechanism by which this gene induces transformation. Reports from this and other laboratories have presented conflicting data regarding the requirement for a known SH2-binding motif, which is found within the transmembrane domain of the JSRV env gene, in cellular transformation. However, these reported events have been observed in fibro-

*From the Department of Microbiology, Immunology, & Pathology (Drs. DeMartini, Ms. Platt, and Mr. Allen), Colorado State University, Fort Collins, CO; and National Jewish Medical and Research Center (Ms. Evans and Mr. Voelker), Denver, CO. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: James C. DeMartini, DVM, PhD, Department of Microbiology, Immunology, and Pathology, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 805231619; e-mail: [email protected]

Thomas L. Petty 46th Annual Aspen Lung Conference; Lung Cancer: Early Events, Early Interventions