Lung Adenocarcinoma Originates from Retrovirus Infection of Proliferating Type 2 Pneumocytes during Pulmonary Post-Natal Development or Tissue Repair

PLoS Pathogens

Marcelo de las Heras¹  Massimo Palmarini²  Ousman Ceesay³  Vincenzo Varasano³  Nicola Ferri³  Marco Caporale⁴  Gabriella Di Francesco⁴  Claudio Murgia⁴ 

[1] Dipartimento di Scienze Cliniche Veterinarie, Facolta' di Medicina Veterinaria, Universita' di Teramo, Italy;Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain;Istituto G. Caporale, Teramo, Italy;Medical Research Council – University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom

关键词: Sheep;    Respiratory infections;    Adenocarcinoma of the lung;    Pneumocytes;    Adenocarcinomas;    Confocal microscopy;    Lung;    intrathoracic tumors;    Pulmonary imaging;   

DOI  :  10.1371/journal.ppat.1002014

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer.

【 授权许可】

CC BY