Abstract
Somatostatin receptor-targeting endoradiotherapy offers potential for treating metastatic pheochromocytomas and paragangliomas, an approach likely to benefit from combination radiosensitization therapy. To provide reliable preclinical in vivo models of metastatic disease, this study characterized the metastatic spread of luciferase-expressing mouse pheochromocytoma (MPC) cells in mouse strains with different immunologic conditions. Bioluminescence imaging showed that, in contrast to subcutaneous non-metastatic engraftment of luciferase-expressing MPC cells in NMRI-nude mice, intravenous cell injection provided only suboptimal metastatic spread in both NMRI-nude mice and hairless SCID (SHO) mice. Treatment of NMRI-nude mice with anti-Asialo GM1 serum enhanced metastatic spread due to substantial depletion of natural killer (NK) cells. However, reproducible metastatic spread was only observed in NK cell-defective SCID/beige mice and in hairless immunocompetent SKH1 mice bearing disseminated or liver metastases, respectively. Liquid chromatography tandem mass spectrometry of urine samples showed that subcutaneous and metastasized tumor models exhibit comparable renal monoamine excretion profiles characterized by increasing urinary dopamine, 3-methoxytyramine, norepinephrine and normetanephrine. Metastases-related epinephrine and metanephrine were only detectable in SCID/beige mice. Positron emission tomography and immunohistochemistry revealed that all metastases maintained somatostatin receptor-specific radiotracer uptake and immunoreactivity, respectively. In conclusion, we demonstrate that intravenous injection of luciferase-expressing MPC cells into SCID/beige and SKH1 mice provides reproducible and clinically relevant spread of catecholamine-producing and somatostatin receptor-positive metastases. These standardized preclinical models allow for precise monitoring of disease progression and should facilitate further investigations on theranostic approaches against metastatic pheochromocytomas and paragangliomas.
Highlights
Adrenal pheochromocytomas and extra adrenal paragangliomas (PPGLs) are rare catecholamineproducing tumors of chromaffin cell origin (Lenders et al 2005, Harari & Inabnet 2011, Jemal et al 2011)
To address the above hypothesis, our objective was to characterize the metastatic spread of luciferase-expressing mouse pheochromocytoma (MPC) cells after intravenous injection in mouse strains featuring different immunologic phenotypes and to compare tumor progression, catecholamine excretion and SSTR2 status of different metastases models with a previously established subcutaneous reference model (NMRI-nude mice) (Ullrich et al 2014, 2016)
Correlation analyses (Supplementary Fig. 8A, B, C and D) showed a significant positive linear relationship between tumor volume as determined using MRI (Supplementary information for methodologic details and discussion) and luminescence intensity of subcutaneous MPCLUC/GZ tumors in NMRI-nude mice as well as between tumor volume and luminescence intensity of liver metastases in SKH1 mice. These results indicate that bioluminescence imaging (BLI) allows for semi-quantitative in vivo monitoring of MPCLUC/GZ cellderived subcutaneous tumors and metastases in mice with comparable accuracy
Summary
Adrenal pheochromocytomas and extra adrenal paragangliomas (PPGLs) are rare catecholamineproducing tumors of chromaffin cell origin (Lenders et al 2005, Harari & Inabnet 2011, Jemal et al 2011). In contrast to most other neoplasms, at least 30% of PPGLs have a hereditary background with variable development of metastatic disease dependent on the mutated gene (Lenders et al 2005). Recommended treatment options for metastatic PPGLs include surgery for removing the tumor bulk, different combinations of chemotherapy, endoradiotherapy using [131I]metaiodobenzylguanidine, external radiation therapy to areas such as bone where metastases are not accessible for surgery, embolization to block tumor blood supply and sometimes cryoor radiofrequency ablation. These treatment options are often considered as palliative (PDQ® Adult Treatment Editorial Board)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
