Patterns of Vasculature in Mouse Models of Lung Cancer Are Dependent on Location

Abstract

PURPOSE Preclinical studies of hypoxia are generally done using ectopic xenograft tumors, which behave differently from human tumors. Our previous findings have shown that subcutaneously implanted lung tumors exhibit more hypoxia than their orthotopic implanted or spontaneous K-ras induced counterparts. We hypothesize that differences in hypoxia are due to site-specific differences in vascularity and perfusion. PROCEDURES To compare the presence and functionality of vessels in these tumor models, we studied vascular perfusion in vivo in real time. RESULTS Orthotopically implanted and spontaneous K-ras induced lung tumors showed elevated perfusion, demonstrating vasculature functionality. Little contrast agent uptake was observed within the subcutaneously implanted tumors, indicating vascular dysfunction. These findings were corroborated at the microscopic level with Hoechst33342 and Meca-32 staining. CONCLUSIONS From these observations we concluded that differences in hypoxia in experimental models is related to vessel perfusion. Thus, appropriate selection of preclinical lung tumor models is essential for the study of hypoxia, angiogenesis and therapies targeting these phenomena.

Deletion of Atm in Tumor but not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma

“…These data are consistent with our previous study showing similar growth of autochthonous sarcomas in mice regardless of Atm expression in endothelial cells (14). Xenograft models are known to display site specific variation in vascular perfusion and hypoxia (9), which may explain why Atm loss in endothelial cells affected xenograft tumor growth, but does not impact the growth of lung cancer or sarcomas (14) in autochthonous model systems.…”

“…In addition, xenografts implanted into mice with defects in the ceramide-mediated endothelial cell apoptosis pathway were resistant to large doses of radiation, suggesting that endothelial cell death was a major determinant of the tumor response to radiotherapy (8). However, the patterns of vascularization in subcutaneous implants may differ from that in primary cancers, which may affect perfusion, oxygenation, and radiation response (9).…”

The effect of flow on blood oxygen level dependent (R*2) MRI of orthotopic lung tumors

“…This is also distinct from the vasculature reported for A549 growing subcutaneously in nude mice . Others have reported substantially different patterns of vasculature and hypoxia in lung tumors developing spontaneously in transgenic mice or implanted subcutaneously or orthotopically . The significantly higher in A549 tumors is consistent with extensive vasculature.…”

Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma

“…In a subcutaneous model of in vivo lung cancer, vascular permeability and perfusion are lower than those in the orthotopic model [ 49 ]. Another study reported that median oxygenation in tumor tissues of NSCLC patients was higher when compared to that in other solid tumors [ 50 ]. Accordingly, to increase accuracy in the assessment of antitumor efficacy and to generate results of radiation therapy associated with hypoxia, it is important to establish a tumor model with conditions similar to those of human lung cancer.…”