In Vivo Fluorescence Imaging and Urinary Monoamines as Surrogate Biomarkers of Disease Progression in a Mouse Model of Pheochromocytoma

Pheochromocytoma is a rare but potentially lethal neuroendocrine tumor arising from catecholamine producing chromaffin cells.Especially for metastatic pheochromocytoma,the availability of animal models is essential for developing novel therapies. For evaluating therapeutic outcome in rodent pheochromocytoma models reliable quantification of multiple organ lesions depends on dedicated small animal in vivo imaging, which is still challenging and only available at specialized research facilities. Here, we investigated whether whole-body fluorescence imaging and monitoring of urinary free monoamines provide suitable parameters for measuring tumor progression in a murine allograft model of pheochromocytoma. We generated an mCherry-expressing mouse pheochromocytoma cell line by lentiviral gene transfer. These cells were injected subcutaneously into nude mice to perform whole-body fluorescence imaging of tumor development. Urinary free monoamines were measured by liquid chromatography with tandem mass spectrometry. Tumor fluorescence intensity and urinary outputs of monoamines showed tumor growth-dependent increases (<0.001) over the 30 days of monitoring post tumor engraftment. Concomitantly, systolic blood pressure was increased significantly during tumor growth. Tumor volume correlated significantly (<0.001) and strongly with tumor fluorescence intensity (=0.946) and urinary outputs of dopamine (=0.952), methoxytyramine (=0.947), norepinephrine (=0.756) and normeta-nephrine (=0.949). Dopamine and methoxytyramine outputs allowed for detection of lesions at diameters below 2.3 mm. Our results demonstrate that MPC-mCherry cell tumors are functionally similar to human pheochromocytoma. Both tumor fluorescence intensity and urinary outputs of free monoamines provide precise parameters of tumor progression in this subcutaneous mouse model of pheochromocytoma. This animal model will allow for testing new treatment strategies for chromaffin cell tumors.