Potential Limitations of Bioluminescent Xenograft Mouse Models: A Systematic Review

Abstract

Purpose: Bioluminescent imaging (BLI) is a versatile technique that offers non-invasive and real-time monitoring of tumor development in preclinical cancer research. However, the technique may be limited by several factors that can lead to misinterpretation of the data. This review aimed to investigate the validity of current BLI tumor models and provide recommendations for future model development. Methods: Two major databases, MedLine and EMBASE, were searched from inception to July 2018 inclusively. Studies utilizing mouse xenograft models with demonstration of linear correlations between bioluminescent signal and tumor burden were included. Coefficients of correlation and determination were extracted along with data relating to animal model parameters. Results: 116 studies were included for analysis. It was found that the majority of models demonstrate good correlation regardless of the model type. Selection of a single cell clone with highest luciferase expression resulted in a significantly better correlation. Lastly, appropriate tumor measurement techniques should be utilized when validating the BLI model. Conclusions: In general, BLI remains a valid tool for pre-clinical assessment of tumor burden. While no single factor may be identified as a general limitation, data should be interpreted with caution.

Validation of Dual Energy X-ray Absorptiometry for longitudinal quantification of tumor burden in a murine model of pancreatic ductal adenocarcinoma

“…Longitudinal assessment via BLI following orthotopic implantation of tumor cells into the pancreas of mice confirmed the robust sensitivity to tumor cell engraftment, as strong signal was detected 1 week after implantation (Figure 2). However, no remarkable increase in BLI signal was detected thereafter, and some time points did not have detectable BLI signal, which is consistent with the established paradigm that BLI is primarily a biomarker of KCKO-Luc cell metabolic activity rather than PDAC tumor mass in this model(7, 9).…”

Validation of a combined ultrasound and bioluminescence imaging system with magnetic resonance imaging in orthotopic pancreatic murine tumors

“…BLI, however, is incapable of resolving internal organs, and may be challenged by signal attenuation for tumors growing inside the body cavity resulting in poor correlation to tumor volume 7 , 8 . Indeed, a recent review recommended that BLI should always be paired with an appropriate non-BLI assessment method to confirm tumor burden measurements 9 .…”

CT vs. bioluminescence: A comparison of imaging techniques for orthotopic prostate tumors in mice

“…In fact, bioluminescent imaging measurements were highly variable in our LNCaP model. Bioluminescence has proven to be a reliable method for many tumor models, including orthotopic models, but there are certain models where bioluminescence does not accurately measure a growing tumor [13]. Previous studies have shown a bioluminescent plateau, where signal detects a mass but underestimates total burden as size increases [20,21].…”

“…found in some orthotopic tumor studies [13]. Additionally, signal detection requires either bioluminescent transfection or fluorescent tagging.…”

“…The bioluminescent technique was developed, and its accuracy was reported, using subcutaneous tumor implants [11,12]. While bioluminescence has shown correlation to actual tumor volume in orthotopic models, it is more variable [12,13]. Accurately measuring tumors becomes challenging when characterizing orthotopic growth, particularly when tumors start to grow beyond normal anatomical scope, as they can grow to large sizes without impeding animal movement or viability.…”