Ovine pulmonary adenocarcinoma as an animal model for human lung adenocarcinoma.

摘要

Appropriate animal models of disease allow defined and controlled investigations that can ultimately be applied to the management of human disease. Based on symptomatic, histopathologic, and possible molecular signaling similarities, we hypothesized that sheep experimentally affected by OPA are a relevant animal model for the study of human lung adenocarcinoma and, in particular, for the evaluation of lung cancer therapeutics. The value of this model is dependent upon its predictability, reproducibility, amenability, and validity. The former two features have been previously reported; OPA induction in sheep is both predictable and reproducible following JSRV inoculation of neonatal lambs. The overall objective of this body of work was to assess the amenability of this animal model for therapeutic research and to assess the validity of OPA-affected sheep as an animal model for human lung adenocarcinoma in terms of genetic similarities.;In addition to assessing the amenability of OPA-affected sheep for therapeutic research, we also found that OPA tumors do not harbor genetic mutations in the TK domain of the EGFR, KRAS codons 12 and 13, or the DNA-binding domain of P53 and therefore, are not genetically similar to human lung adenocarcinomas that contain these mutations. Based on these genetic disparities, OPA-affected sheep are not an ideal animal model for human lung adenocarcinoma. Overall, the genetic profile combined with the disease development data provided further characterization of OPA and facilitated an assessment of the utility and relevance of this animal model for human lung cancer studies.;We determined that this animal model is amenable for therapeutic studies because, using CT, OPA can be detected early, before the onset of clinical signs, and cancer development can be monitored noninvasively. However, not only did we observe OPA disease progression during this study, but surprisingly, we also witnessed spontaneous regression of OPA. In fact, the latter was the more common outcome seen in our research after JSRV inoculation of neonatal lambs. We propose that the immune system, particularly CD3+ T-cells, is an important mediator of the spontaneous regression of JSRV-induced OPA seen in our work. Regardless of the cause, the mere occurrence of spontaneous regression of cancer in OPA-affected sheep severely restricts the use of this animal model for therapeutic research.