Characterization of a highly metastatic, orthotopic lung cancer model in the nude rat

The prevailing subcutaneous nude rodent tumor xenograft models used for bio logical and preclinical studies do not optimally reflect some important bio logical properties of cancer, especially invasion and metastasis. Orthotopi c models have been developed to address this need. However, for lung cancer none of the available models are optimal, in that none originate from an o rthotopic (bronchial) primary site and exhibit extensive extrathoracic meta stasis. Our goal was to develop a consistent rodent model of non-small cell lung cancer with both of these properties. Groups of male Rowett nude rats were given 500 rads of gamma radiation and then endobronchially implanted in the right caudal lobe airway with 50 mg of small NCI-H460 tumor fragment s taken from an orthotopic donor tumor. They were then sacrificed at select ed post-implantation times and evaluated grossly and histologically for ani mal weight, primary tumor take and size, and metastatic tumor incidence at multiple sites. At a late time point (32-35 days), consistency of primary t umor size and metastasis was estimated by comparing results from four group s of rats implanted on different occasions. The results showed that the pri mary tumors grew steadily, reaching four grams by days 32-35. Rats gained w eight until days 14 to 21, but then began to show cachexia. High metastatic rates (> 60%) were seen for mediastinal lymph nodes (by 21 days), and kidn ey, bone and brain (by 28 days). Mean primary tumor size and the incidences of both regional and systemic metastasis were consistent at 32-35 days in four different groups of six animals. In conclusion, this orthotopic lung c ancer model is highly metastatic and consistent in terms of both primary tu mor growth and metastatic behavior. It is the only available rodent model o f human lung cancer emanating from an endobronchial site and metastasizing to multiple extrapulmonary sites, and should be very useful for both biolog ical and preclinical studies of lung cancer, particularly where studies of antimetastatic activity are of interest, and/or where survival studies are desired.