Ovine Pulmonary Adenocarcinoma: A Unique Model to Improve Lung Cancer Research

Abstract

Lung cancer represents a major worldwide health concern; although advances in patient management have improved outcomes for some patients, overall 5-year survival rates are only around 15%. In vitro studies and mouse models are commonly used to study lung cancer and their use has increased the molecular understanding of the disease. Unfortunately, mouse models are poor predictors of clinical outcome and seldom mimic advanced stages of the human disease. Animal models that more accurately reflect human disease are required for progress to be made in improving treatment outcomes and prognosis. Similarities in pulmonary anatomy and physiology potentially make sheep better models for studying human lung function and disease. Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer that is caused by the jaagsiekte sheep retrovirus. The disease is endemic in many countries throughout the world and has several features in common with human lung adenocarcinomas, including histological classification and activation of common cellular signaling pathways. Here we discuss the in vivo and in vitro OPA models that are currently available and describe the advantages of using pre-clinical naturally occurring OPA cases as a translational animal model for human lung adenocarcinoma. The challenges and options for obtaining these OPA cases for research purposes, along with their use in developing novel techniques for the evaluation of chemotherapeutic agents or for monitoring the tumor microenvironment in response to treatment, are also discussed.

Keywords: comparative oncology; human lung cancer; jaagsiekte sheep retrovirus; ovine pulmonary adenocarcinoma; sheep lung cancer models.

Figure 1

Ovine and human comparative gross anatomy. (A) Ovine lower respiratory tract. (B) Human lower respiratory tract.

Figure 2

Histological appearance of OPA tumors. (a–c) OPA haematoxylin and eosin stained sections. (a) Columnar tumor cells can be seen lining the alveolar septa (black arrows), forming acinar, or papillary proliferations. Two groups of neutrophils are present between the tumor cells (red arrows). (b) Alveolar macrophages can be seen at the top right-hand side of the image and are characterized by large amounts of foamy cytoplasm. (c) Accumulation of mononuclear immune cells, mostly lymphocytes, and plasma cells, can be observed at the top left-hand side of the image. (d) Masson's trichrome stained section. Collagen is stained blue and can be identified surrounding the tumor cells (yellow arrow heads), acting as a scaffold for the influx of inflammatory cells.

Figure 3

Gross pathology of OPA tumors. (a,b) Large single advanced OPA tumors affecting the entire left cranial lung lobe. The lesions are gray in color with a clear distinct boundary between neoplastic tissue and the neighboring pink aerated lung. Extensive fibrous tissue can be seen attached to the overlying pleura of the tumor. (c) Two discrete OPA tumors within the right cranial and caudal lung lobes.

Figure 4

Thoracic CT images of OPA tumors. (a) Axial, (b) Coronal, and (c) Sagittal planes. Three large areas of increased radiopacity are seen within the lung lobes consistent with advanced OPA tumors (outlined in red). One lesion is present within the dorsal region of the left cranial lung lobe with a further lesion in the ventral region of the left caudal lung lobe. A smaller lesion is present within the right caudal lung lobe. A patchy and hazy area of increased opacity (ground glass appearance), with preservation of bronchial and vascular patterns, is present (outlined in yellow) between the two tumors in the left lung lobes. This area is consistent with regions of neoplastic foci or a secondary pneumonia.