Abstract
BackgroundXenograft mouse tumor models are used to study mechanisms of tumor growth and metastasis formation and to investigate the efficacy of different therapeutic interventions. After injection the engrafted cells form a local tumor nodule. Following an initial lag period of several days, the size of the tumor is measured periodically throughout the experiment using calipers. This method of determining tumor size is error prone because the measurement is two-dimensional (calipers do not measure tumor depth). Primary tumor growth can be described mathematically by suitable growth functions, the choice of which is not always obvious. Growth parameters provide information on tumor growth and are determined by applying nonlinear curve fitting.MethodsWe used self-generated synthetic data including random measurement errors to research the accuracy of parameter estimation based on caliper measured tumor data. Fit metrics were investigated to identify the most appropriate growth function for a given synthetic dataset. We studied the effects of measuring tumor size at different frequencies on the accuracy and precision of the estimated parameters. For curve fitting with fixed initial tumor volume, we varied this fixed initial volume during the fitting process to investigate the effect on the resulting estimated parameters. We determined the number of surviving engrafted tumor cells after injection using ex vivo bioluminescence imaging, to demonstrate the effect on experiments of incorrect assumptions about the initial tumor volume.ResultsTo select a suitable growth function, measurement data from at least 15 animals should be considered. Tumor volume should be measured at least every three days to estimate accurate growth parameters. Daily measurement of the tumor volume is the most accurate way to improve long-term predictability of tumor growth. The initial tumor volume needs to have a fixed value in order to achieve meaningful results. An incorrect value for the initial tumor volume leads to large deviations in the resulting growth parameters.ConclusionsThe actual number of cancer cells engrafting directly after subcutaneous injection is critical for future tumor growth and distinctly influences the parameters for tumor growth determined by curve fitting.
Highlights
Xenograft mouse tumor models are used to study mechanisms of tumor growth and metastasis formation and to investigate the efficacy of different therapeutic interventions
The actual number of cancer cells engrafting directly after subcutaneous injection is critical for future tumor growth and distinctly influences the parameters for tumor growth determined by curve fitting
As an example of using a fixed vs. non-fixed initial volume during the fitting procedure, Fig. 1 shows growth curves of fits on a single synthetic sample with different measurement frequencies compared to the true volume which represent the synthetic tumor growth with the true set of growth parameters without measurement errors
Summary
Xenograft mouse tumor models are used to study mechanisms of tumor growth and metastasis formation and to investigate the efficacy of different therapeutic interventions. The variations between groups in the mean values of primary tumor size measured on different days are considered to be indicators of differences in, for example, the effectiveness of a drug treatment [3,4,5,6] Sometimes data from these experiments are fitted to mathematical growth functions to describe and predict the growth of the tumor [7,8,9]. Another possible effect may be variation in the growth parameters caused by, for example, slight differences in location of the engrafted cells affecting their proximity to the nearest blood vessels It is questionable whether the common approach of only using the mean values of primary tumor size measured on different days can deliver valid results, or whether the observed differences represent random variations of the number of engrafted cells. A systematic evaluation of whether this approach is delivering reliably accurate results, and under which circumstances these can be obtained, is the subject of the research presented in this article
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