Complications associated with the development of lung
metastases have a detrimental effect on the overall survival rate of many
cancer patients. Preclinical models that mimic the clinical aspects of lung
metastases are an important tool in developing new
therapy options for these patients. The commonly used intravenous models only recapitulate dissemination of
cancer cells to the lungs via the haematological route. Here we compared spontaneous and intravenous lung
metastases of the highly metastatic KHT mouse
fibrosarcoma cells after injecting KHT cells into the subcutaneous layer of the skin or directly into the tail vein. In contrast to the intravenous model,
metastases spontaneously arising from the subcutaneous tumours disseminated most consistent with the lymph nodes/lymphatics route and were more hypoxic than the
metastases observed following tail-vein administration and haematological spread. To ascertain whether this impacted on
drug response, we tested the effectiveness of the
hypoxia-sensitive
cytotoxin AQ4N (
Banoxantrone) in both models.
AQ4N was more effective as an anti-metastatic
drug in mice with subcutaneous KHT tumours, significantly reducing the metastatic score. Complementing the KHT studies, pathology studies in additional models of spontaneous lung
metastases showed haematological (HCT116 intrasplenic implant) or mixed haematological/lymphatic (B16 intradermal implant) spread. These data suggest that preclinical models can demonstrate differing, clinically relevant dissemination patterns, and that careful selection of preclinical models is required when evaluating new strategies for targeting metastatic disease.