Intranasal Administration of Type V Collagen Reduces Lung Carcinogenesis through Increasing Endothelial and Epithelial Apoptosis in a Urethane-Induced Lung Tumor Model

Abstract

Type V collagen (Col V) is a "minor" component of normal lung extracellular matrix, which is subjected to decreased and abnormal synthesis in human lung infiltrating adenocarcinoma. We previously reported that a direct link between low amounts of Col V and decreased cell apoptosis may favor cancer cell growth in the mouse lung after chemical carcinogenesis. Moreover, this collagen species was able to trigger DNA fragmentation and impair survival of neoplastic cells. In this study, we have extended our investigation with the aim to obtain further evidence that the death induced by Col V-treatment is of the caspase-9 apoptotic type. We used (1) optical and electron microscopy, (2) quantitation of TUNEL-labeled cells and (3) analysis of the expression levels of Col V and selected genes coding for apoptosis-linked factors, by conventional RT-PCR. BALB/c mice were injected intraperitoneally with 1.5 g/kg body weight of urethane. After urethane injection, the animals received intranasal administration of 20 µg/20 µl of Col V every day during 2 months. We report here that Col V treatment was able to determine significant increase in Col V protein and gene expression and in the percentage of TUNEL-positive cells, to up-regulate caspase-9, resulting in low growth of tumor cells. Our data validate chemical carcinogenesis as a suitable "in vivo" model for further and more detailed studies on the molecular mechanisms of the death response induced by Col V in lung infiltrating adenocarcinoma opening new strategies for treatment.

The Effect of Vanadium Inhalation on the Tumor Progression of Urethane-Induced Lung Adenomas in a Mice Model

“…The urethane model for lung tumors is a chemical carcinogenesis method that has been used to study tumor progression and treatments [9][10][11].…”

“…Recently other optional routes for drug delivery have been proposed for the treatment of diverse pathologies [17] such as lung cancer [11]. Hamzawy et al reported intratracheal administration of temozolomide in lung tumors induced by urethane [18] and Roger-Parra intranasally delivered anti-collagen-V for lung cancer treatment with promising results [11].…”

“…Aerosol drug delivery has been a technique used for the treatment of a variety of diseases and recently for experimental antineoplastic therapies [11]. This route increases the bioavailability and decreases the time of action because the doses decrease the risk of side effects, and the drug reaches the lung tissue without the metabolic changes that occur in the liver [19,20].…”